14β-Hydroxyandrostanes

ABSTRACT

14β-Hydroxyandrostanes and processes for the preparation thereof in which the 14β-hydroxy group is fabricated internally by means of a novel cyclization of 8,14-seco-4,6,9(11)-androstatrien-3,14,17-triones is disclosed. 
     The 14β-hydroxyandrostanes are useful as precursors for the synthesis of cardenolides and related products.

This is a division of application Ser. No. 811,393 filed June 29, 1977,now U.S. Pat. No. 4,134,920 issued Jan. 16, 1979.

BACKGROUND OF THE INVENTION

The cardenolides are a group of cardio-active steroids characterized bythe presence of a 14β-hydroxyl function and a 17β-butenolide moiety("Steroids," L. F. Fieser and M. Fieser, Reinhold PublishingCorporation, New York, New York, 1959, ch. 20). Many of these compounds,which occur in small amounts in various plants, are potent cardiacstimulants (G. K. Moe and A. E. Farah, in "The Pharmacological Bases ofTherapeutics," 4th Ed., L. S. Goodman and A. Gilman, ed., The MacmillanCompany, New York, New York, 1970, ch. 31), and for this reason,considerable synthetic effort directed toward their synthesis has beenexpended in the past. Prior to 1962, the fruits of these labors havebeen minimal. While methods for the introduction of the 14β-hydroxygroup and the construction of the 17β-butenolide have been developedutilizing model compounds, they have been uniformly inapplicable in thenatural series. In 1962, the problems associated with theconfigurational instability of the 17β-butenolide and the lability ofthe 14β-hydroxy function during construction of the butenolide wereresolved in the first reported synthesis of a cardenolide,digitoxigenin. This synthesis, while recognized as a scientificbreakthrough, suffers from the disadvantage of starting from difficultyavailable materials resulting in low overall yields (R. Deghenghi, Pureand Appl. Chem., 21, 153 [1970]). Since 1962, improved syntheses ofcardenolides have been reported. These syntheses, like the originalsynthesis of digitoxigenin, however, start with preformed steroids,involve the direct introduction of the 14β-hydroxyl group and sufferfrom the predominant disadvantage of the unavailability of the precursorsteroids. Thus, an efficient synthesis of 14β-hydroxysteroidylcardenolide precursors, making ultimate cardenolides readily availablefor therapeutic use, would be a major advance in this area (P. J. Sykesand S. J. Whitehurst, in "Terpenoids and Steroids," K. H. Overton, ed.,Volume 5, The Chemical Society, London, England, 1975, page 354).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel 14β-hydroxyandrostanes and novel,efficient processes for the operation thereof. More particularly, thepresent invention relates to 14β-hydroxy-4,6,9(11)-androstatrienes,14β-hydroxy-4,9(11)-androstadienes and 14β-hydroxy-9(11)-androstenes andprocesses for the preparation thereof involving the steps of convertinga 1-hydroxy-8a-loweralkyl-1-vinyl-1,2,3,4,6,7,8,8a-octahydro-6-naphthalenone to a1-(2-chloroethylidene)-8a-loweralkyl-1,2,3,4,6,7,8,8a-octahydro-6-naphthalenone, condensing the1-(2-chloroethylidene)-8a-loweralkyl-1,2,3,4,6,7,8,8a-octahydro-6-naphthalenone with a 2-loweralkyl-1,3-cyclopentadione to form a8,14-seco-4,9(11)-androstadiene-3,14,17-trione, dehydrogenating the8,14-seco-4,9(11)-androstadiene-3,14,17-trione to8,14-seco-4,6,9(11)-androstatriene-3,14,17-trione, cyclizing the8,14-seco-4,6,9(11)-androstatriene-3,14,17-trione to a14β-hydroxy-4,6,9(11)-androstatriene-3,17-dione, hydrogenating the14β-hydroxy-4,6,9(11)-androstatriene-3,17-dione to a14β-hydroxy-4,9(11)-androstadiene-3,17-dione and chemically reducing andthen oxidizing the 14β -hydroxy-4,9(11)-androstadiene-3,17-dione to a14β-hydroxy-9(11)-androstene-3,17-dione. The present invention, alsomore particularly, relates to an alternative process for the preparationof 8,14-seco-4,6,9(11)-androstatriene-3,14,17-trione involving the stepsof dehydrogenating 1-hydroxy-8a-loweralkyl-1-vinyl-1,2,3,4,6,7,8,8a-octahydro-6-naphthalenone to a1-hydroxy-8a-methyl-1-vinyl-1,2,6,7,8,8a-hexahydro-6-naphthalenone,converting the1-hydroxy-8a-methyl-1-vinyl-1,2,6,7,8,8a-hexahydro-6-naphthalenone to a1-(2-haloethylidene)-8a-methyl-1,2,6,7,8,8a-hexahydro-6-naphthalenoneand condensing the1-(2-haloethylidene)-8a-methyl-1,2,6,7,8,8a-hexahydro-6-naphthalenonewith a 2-lower alkyl-1,3-cyclopentadione to form the8,14-seco-4,6,9(11)-androstatriene-3,14,17-trione.

As used throughout the specfication and appended claims, the term"alkane" refers to a straight or branched chain hydrocarbon such asmethane, ethane, 2-butane, hexane, 2-octane and so forth. The term"alkyl" refers to a radical derived by abstraction of a hydrogen atomfrom an alkane. Examples of "alkyl" radicals are methyl, ethyl,tert.-butyl, hexyl, 2-octyl and so forth. The term "alkanol" refers toan alcohol derived by replacement of a hydrogen atom of an alkane by ahydroxy radical. Examples of alkanols are methanol, ethanol, 2-butanol,hexanol, 2-octanol and so forth. The term "alkoxide" refers to the anionderived by abstraction of a proton from the hydroxyl group of analkanol. Examples of alkoxides are methoxide, ethoxide, 2-butoxide,hexoxide, 2-octoxide and so forth. The term "alkanoic acid" refers to acarboxylic acid derived by replacement of a hydrogen atom of an alkaneby a carboxylic acid group. Examples of alkanoic acids are acetic acid,2,2-dimethylacetic acid, hexanoic acid, octanoic acid and so forth. Theterm "lower" refers to the numerical range of 1 to 8.

In the formulas presented therein, the relative stereochemistry of thevarious substituents on the cyclic nucleus is indicated by one of threenotations: a solid line (--), indicating the substituent is in theβ-orientation, i.e., above the plane of the molecule; a dotted line( - - - - ), indicating the substituent is in the α-orientation, i.e.,below the plane of the molecule; or a wavy line ( ), indicating thesubstituent may be either in the α- or β-configuration or may be amixture of both.

For convenience, the stereochemistry of the substituent R₁ at the C-10position (steroid numbering) has been arbitrarily indicated as theβ-orientation; thus all the compounds are depicted as having the naturalabsolute configuration. It should be understood that the inventiondescribed herein is equally applicable to compounds having either thenatural or the unnatural configuration, for example, to racemicmixtures.

If it is desired to prepare optically active steroids, one may eitherbegin with a known optically active compound of formula 1 ##STR1##wherein R₁ is lower alkyl or alternatively, one may start with a racemiccompound of formula 1 and may carry out an optical resolution at one ofthe intermediate stages, or at the stage of the final product by methodsknown per se.

The processes of the present invention for the preparation of14β-hydroxyandrostanes are illustrated in the Reaction Scheme. ##STR2##wherein R₁ and R₂ are each independently lower alkyl; X is chloro orbromo, and M.sup.⊕ is an alkali metal.

In the first step of the instant process, a 1-hydroxy-8a-lower alkyloctahydro-6-naphthalenone of formula I, the preparation of which isdescribed by S. Swaminathan et al., Tetrahedron Letters, 729 (1962), istreated with thionyl chloride to give a 1-(2-chloroethylidene)-8a-loweralkyl-1,2,3,4,6,7,8,8a-octahydro-6-naphthalenone of formula 2. Thedisplacement-rearrangement reaction is generally conducted by dissolvingthe vinyl carbinol in a halocarbon, such as methylene chloride,chloroform, 1,2-dichloroethane, 1,1-dichloroethane and the like, at areduced temperature of about 0° C. to about -70° C. and then adding asolution of a polar aprotic solvent, such as N,N-dimethylacetamide,N,N-dimethylformamide, hexamethylphosphoramide and the like, in ahalocarbon, such as methylene chloride, chloroform, 1,2-dichloroethane,1,1-dichloroethane and the like, also at a temperature of about 0° C. toabout -70° C. The reaction is preferably carried out in methylenechloride using N,N-dimethylformamide as the polar aprotic solvent at atemperature of about -60° C.

The preparation of1-(2-bromoethylidene)-8a-methyl-1,2,3,4,6,7,8,8a-octahydro-6-naphthalenonehas been reported by J. Ruppert et al. in Chem. Ber., 106, 3636 (1973).

In the second step, the allylic chloride of formula 2 is condensed withan alkali metal salt, such as the lithium, sodium or potassium salt, ofa 2-lower alkylcyclopentandione-1,3of formula 3 to afford aseco-androstadiene of formula 4. The condensation is suitably performedin the presence of an alkali metal iodide, such as lithium, sodium orpotassium iodide, by treating a solution of the chloride of formula 2and the alkali metal iodide dissolved in a polar aprotic solvent such asN,N-dimethylbutamide, N,N-dimethylformamide, hexamethylphosphoramide andthe like, with a solution of the alkali metal salt of the dione offormula 3 dissolved in a lower alkanol, such as methanol, ethanol,2-propanol and the like. The condensation is preferably carried out inN,N-dimethylformamide using sodium iodide and the sodium salt of thedione of formula 3 dissolved in methanol.

The alkali metal salt of the 2-lower alkylcyclopentadione-1,3 of formula3 may be conveniently prepared by treating the dione of formula 3 withan alkali metal lower alkoxide, such as lithium methoxide, sodiummethoxide, sodium ethoxide, potassium 2-butoxide and the like, in alower alkanol, such as methanol, ethanol, 2-butanol and the like. It ispreferable to employ the lower alkanol from which the alkoxide isderived. It is most preferable to employ sodium methoxide in methanol.

Optically active 8,14-seco-4,9(11)-androstadiene-3,14,17-trione, thecompound of formula 4 wherein R₁ and R₂ are methyl, has been prepared byJ. Ruppert et al. (Chem. Ber., 106, 3636 [1973]) by a related process inan inferior yield.

In the third step of the present process, the 6,7-double bond (steroidnumbering) is introduced by dehydrogenation of an8,14-seco-androstadiene of formula 4. This step is generallyaccomplished by treatment of the 8,14-seco-androstadiene with ap-quinone, such as 1,4-benzoquinone, 1,4-naphthaquinone,2,3,5,6-tetrachloro-1,4-benzoquinone,2,3-dichloro-5,6-dicyano-1,4-benzoquinone,2,3-dibromo-5,6-dicyano-1,4-benzoquinone and the like, in an inertorganic solvent, for example, an ethereal solvent, such astetrahydrofuran, dioxane, 1,2-dimethoxyethane, bis-(2-methoxyethyl)etherand the like. 2,3-Dichloro-5,6-dicyano-1,4p-benzoquinone is thepreferred dehydrogenation agent. Dioxane is the preferred reactionsolvent.

To promote the dehydrogenation, i.e., the conversion of a seco-steroidof formula 4 to a seco-steroid of formula 5, a catalytic amount of astrong mineral acid, such as hydrogen chloride, hydrogen bromide and thelike, or a sulfonic acid, such as methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid and the like, may be added to the reactionmixture. About 0.2% by weight of hydrogen chloride in an inert organicsolvent is the preferred promoter.

Alternatively, the 8,14-seco-androstatriene of formula 5 may be preparedby a comparable series of reaction in which the 6,7-double bond of theultimate seco-steroid is constructed in the initial step of the processand carried through to the final product. In the first step of thealternative process, a 1-hydroxy-8a-loweralkyl-1-vinyl-1,2,3,4,6,7,8,8a-octahydro-6-naphthalenone of formula 1 isdehydrogenated to a 1-hydroxy-8a-loweralkyl-1-vinyl-1,2,6,7,8,8a-hexahydro-6-naphthalenone of formula 11. Thedehydrogenation is performed employing a p-quinone in an inert organicsolvent. Suitable p-quinones include 1,4-benzoquinone,1,4-naphthaquinone, 2,3,5,6-tetrachloro-1,4-benzoquinone,2,3-dichloro-5,6-dicyano-1,4-benzoquinone,2,3-dibromo-5,6-dicyano-1,4-benzoquinone and the like. Suitable inertsolvents include, for example, ethereal solvents, such astetrahydrofuran, dioxane, 1,2-dimethoxyethane, bis-(2-methoxyethyl)etherand the like. A strong mineral acid, such as hydrogen chloride, hydrogenbromide and the like, or a sulfonic acid, such as methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid and the like, may beutilized in catalytic amounts to promote the dehydrogenation. Thereaction is preferably conducted in dioxane containing about 0.4% byweight of hydrogen chloride using2,3-dichloro-5,6-dicyano-1,4-benzoquinone as the dehydrogenating agent.

The hexahydro-6-naphthalenone of formula 11, so-obtained, is thensubstitutively-rearranged by means of a thionyl halide of formula 12 inan inert organic solvent, for example, a halocarbon, such as methylenechloride, chloroform, 1,1-dichloroethane, 1,2-dichloroethane and thelike. Thionyl chloride dissolved in methylene chloride is the preferredreaction system.

An organic base, such as triethyl amine, pyridine, s-collidine and thelike may be employed in the substitution-rearrangement to scavengeformed hydrogen halide. Pyridine is the preferred scavenger.

While the temperature at which the substitution-rearrangement isperformed is not narrowly critical, it is preferred to conduct thereaction at a reduced temperature within the range of about -40° toabout 20° C., a temperature of about 0° C. being particularly preferred.

To complete the alternative synthesis of the seco-androstatriene offormula 5, the allylic halide of formula 13 is condensed with an alkalimetal salt, for example, the lithium, sodium or potassium salt, of a2-lower alkylcyclopentadione-1,3-of formula 3 to afford the seco-steroidof formula 5. Like the condensation of the allylic chloride of formula 2with the alkali metal salt of a 2-lower alkylcyclopentandione-1,3 offormula 3 to furnish the seco-steroid of formula 4, the instantcondensation is suitably conducted in the presence of an alkali metaliodide, such as lithium, sodium or potassium iodide, by treating asolution of the halide of formula 13 and the alkali metal iodidedissolved in a polar aprotic solvent, such as N,N-dimethylacetamide,N,N-dimethylformamide, hexamethylphosphoramide and the like, with asolution of the alkali metal salt of the dione of formula 3 dissolved ina lower alkanol, such as methanol, ethanol, 2-propanol and the like.This condensation, also like that performed with the allylic chloride offormula 2, is preferably carried out in N,N-dimethylformamide usingsodium iodide and the sodium salt of the dione of formula 3 dissolved inmethanol.

In the next step of the primary process of the present invention, theseco-androstatriene of formula 5 is cyclized to the14β-hydroxy-4,6,9(11)-androstatriene-3,17-dione of formula 6 under basicconditions. The cyclization is generally performed by dissolving theseco-steroid of formula 5 in a suitable solvent, for example, a loweralkanol, such as methanol, ethanol, 2-butanol and the like and thenadjusting the pH to a value within the range of 7.5-12 units by adding abase, for example, an alkali metal alkoxide, such as lithium methoxide,sodium methoxide, sodium ethoxide, potassium butoxide and the like. Thecyclization is preferably conducted in methanol containing sufficientsodium methoxide to attain a reaction pH within the range of 8.0-9.5units.

The 6,7-double bond of the 14β-hydroxyandrostatriene of formula 6 isthen hydrogenated to the 14β-hydroxyandrostadiene of formula 7. Thehydrogenation is conveniently conducted at a pressure of from about 1atmosphere to about 5 atmospheres of hydrogen and a temperature withinthe range of about 20° to about 50° C. in the presence of a metalhydrogenation catalyst, such as, for example, platinum, palladium,rhodium, ruthenium and the like, in a suitable inert solvent. Suitableinert solvents include aromatic hydrocarbons, such as benzene, toluene,xylene and the like, and alkanols, such as methanol, ethanol, 2-butanoland the like. The hydrogenation is preferably conducted at a pressure ofabout 1 atmosphere of hydrogen and at a temperature of about 25° C.using a palladium catalyst suspended in a solvent comprising benzene andethanol. A particularly preferred hydrogenation catalyst is 2%palladium-on-strontium carbonate.

An isomeric 14-hydroxy-4,9(11)-androstadien-3,17-dione was recentlydisclosed by J. Ruppert et al., in Chem. Ber., 106, 3636 (1973). Thereported isomer of 14β-hydroxy-4,9(11)-androstadien-3,17-dione of thepresent invention is most probably either the 8- or 13,14-epimer of theandrostadiene of the present invention and therefore not useful for thepreparation of natural cardenolides.

In the next step of the instant process for the preparation of14β-hydroxyandrostanes, the 14β-hydroxyandrostadien-3,17-dione offormula 7 is reduced to the 14β-hydroxyandrosten-3,17-diol of formula7a, the 3- and 17-hydroxy groups of which are then oxidized to afford a14β-hydroxyandrosten-3,17-dione of formula 8. The reduction aspect ofthis step may be accomplished by means of an alkali metal, for example,lithium, sodium or potassium, or an alkaline earth metal, for example,calcium, dissolved in liquid ammonium or a liquid amine. Alkali metalsare preferred, lithium being most preferred. Suitable liquid aminesinclude methylamine, ethylamine, propylamine, L-propylamine, butylamineand ethylenediamine. Of the liquid amines, ethylamine andethylenediamine are preferred, liquid ammonium being particularlypreferred as the ammonical component.

To solubilize the organic substrate, a cosolvent, for example, anethereal solvent, such as diethyl ether, 1,2-dimethoxyethane,tetrahydrofuran, dioxane and the like, may be employed. Dioxane andtetrahydrofuran are the preferred cosolvents, dioxane being particularlypreferred.

To promote the dissolving metal reduction, a proton source is generallyemployed. Suitable proton sources include lower alkanols, such asmethanol, ethanol, 2-propanol, tert.-butanol and the like. Ethanol andtert.-butanol are preferred. tert.-Butanol is most preferred.

The reduction is usually conducted at the boiling point of the ammonicalcomponent when its boiling point is below room temperature. When theboiling point of the ammonical component is above room temperature, thereaction is generally performed at room temperature, although whenethylenediamine is employed, reaction temperature above room temperaturecan be utilized, for example, from slightly above room temperature tonear the reflux temperature of the diamine.

The oxidation aspect of this step, i.e., the conversion of the14β-hydroxy-androsten-3,17-diol of formula 7a to the14β-hydroxyandrosten-3,17-dione of formula 8, is accomplished by meansof non-acidic oxidizing systems in inert solvents. Suitable non-acidicoxidizing systems include chromic acid-pyridine, pyridiniumchlorochromate and the like. Suitable inert solvents include,halocarbons, such as methylene chloride, chloroform, 1,1-dichloroethane,1,2-dichloroethane and the like. In the preferred embodiment, the14β-hydroxyandrostane of formula 7a is oxidized with pyridiniumchlorochromate in methylene chloride.

In the last step of the present process, the 9(11)-double bond of a14β-hydroxyandrosten-3,17-dione is saturated with hydrogen withconcomitant reduction of the 3-keto group to a hydroxy function to givea 3,14β-hydroxy-androstan-17-one of formula 9. The reduction is suitablyeffected at a hydrogen pressure of from about one atmosphere to about 5atmospheres and a temperature within the range of about 20° to about 50°C. in the presence of a metal hydrogenation catalyst, such as, forexample, platinum, palladium, rhodium, ruthenium and the like, in aninert solvent. Suitable inert solvents include, for example, loweralkanoic acids, such as acetic acid, propionic acid and the like. Thereduction is preferably conducted at a pressure of about one atmosphereof hydrogen and a temperature of about 25° C. using platinum oxidesuspended in glacial acetic acid.

3β,14β-Dihydroxyandrostan-17-one may be converted to the 3-acetylderivative of formula 10 by standard methods well known in the artinvolving reaction with, for example, acetic anhydride in the presenceof a base, such as pyridine. 3β-Acetoxy-14β-hydroxyandrostan-17-one hasbeen converted to the cardenolide, uzarigenin, which exhibits not onlycardiac stimulant activity, but is also useful for the treatment ofdiarrhea and bacillary dysentery (U.S. Pat. No. 3,595,883, issued July27, 1971)

The following examples are illustrative only of the invention and arenot to be construed as limitative thereof in any manner. Alltemperatures are reported in degrees Centigrade.

EXAMPLE 1 Preparation of1-(2-chloroethylidene)-8a-methyl-1,2,3,4,6,7,8,8a-octahydro-6-naphthalenone

1-Hydroxy-8a-methyl-1-vinyl-1,2,3,4,6,7,8,8a-octahydro-6-naphthalenone(17.0 g.) dissolved in 60 ml. of methylene chloride was cooled in a dryice-acetone bath to -60°, and 13.5 g. of thionyl chloride was addeddropwise at this temperature. Then 13.5 ml. of dimethylformamide in 10ml. of methylene chloride was added at -60° to -40° for about two hours.When starting material could not be detected by thin-layerchromatography in the reaction mixture, water was added and the mixturewas washed with an aqueous solution of potassium bicarbonate and thenwith brine. After drying, the solvent was evaporated under reducedpressure and the crude product containing some dimethylformamide wasdissolved in ether and passed through a short column (2 cm.) of aluminato remove polar impurities.

Yield of chloride was about 95%.

N.M.R. (CDCl₃): δ 1.42 (s, 3H, CH₃), 4.12 (d,J=7.7 Hz, 2H, CH₂ Cl), 5.53(d,J=7.7 Hz, 1H, C═CH), 5.77 (s, 1H, --CO--CH═C).

EXAMPLE 2 Preparation of 8,14-seco-4,9(11)-androstadien-3,14,17-trione

Sodium iodide (12 g.) was dissolved in 150 ml. of dimethylformamide anda solution of1-(2-chloroethylidene)-8a-methyl-1,2,3,4,6,7,8,8a-octahydro-6-naphthalenonein 30 ml. of dimethylformamide was added. The mixture was stirred atroom temperature for 30 minutes and then the sodium salt of2-methylcyclopentadione-1,3 in 150 ml. of methanol was added. Alkylationwas complete in 2 hours at room temperature. Methanol was thenevaporated, 1 liter of dry ether was added to the residue and theinorganic precipitate was filtered off and washed with ether. Thefiltrate was evaporated to dryness under reduced pressure and theresidue was passed through a short column of alumina using methylenechloride as a solvent. After evaporation of solvent, the residue wascrystallized from ether to give 14 g. of the seco-androstadiene, m.p.79°-81°. The filtrate was chromatographed on silica to give anadditional 3 g. of product.

The overall yield of seco-androstadiene based on1-hydroxy-8a-methyl-1-vinyl-1,2,3,4,6,7,8,8a-octahydro-6-naphthalenonewas 68.7%.

N.M.R. (CDCl₃): δ 1.10 (s, 3H, CH₃), 1.32 (s, 3H, CH₃), 2.7 (s, 4H,OCCH₂ CH₂ CO), 5.12 (t,J=7.8 Hz, 1H, C-11), 5.73 (s, 1H, C-4).

EXAMPLE 3 Preparation of8,14-seco-4,6,9(11)-androstatrien-3,14,17-trione

To a solution of 8,14-seco-4,9(11)-androstadien-3,14,17-trione (1 g.) in100 ml. of anhydrous dioxane was added 30 ml. of a solution of hydrogenchloride (1% by weight) in anhydrous dioxane. This mixture was stirredat room temperature for 10 minutes and2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.750 g.) in 25 ml. dioxanewas added dropwise during 1 hour. After an additional hour, the mixturebecame light yellow. The precipitate was collected, the filtrate wasneutralized with a saturated aqueous solution of potassium bicarbonateand after drying with sodium sulfate, the solvent was evaporated. Theresidue was dissolved in benzene (50 ml.) and hexane (10 ml.), stirredwith a small amount of charcoal, filtered and the charcoal was washedwith benzene. Evaporation of solvent gave the seco-androstatriene (0.950g.) in 70-80% purity (N.M.R.).

N.M.R. (CDCl₃): δ 1.14 (s, 3H, CH₃ at C-18), 1.27 (s, 3H, CH₃ at C-19),2.69 (s, 4H, O═CCH₂ CH₂ C═O), 3.1 (m, 2H at C-8), 5.16 (t, J=7.8 Hz, 1Hat C-11), 5.74 (s, 1H at C-4), 6.4 (s, 2H at C-6 and C-7). U.V.: λ_(max)284 nm.

EXAMPLE 4 Preparation of 14β-hydroxy-4,6,9(11)-androstatrien-3,17-dione

To a solution of 8,14-seco-4,6,9(11)-androstatrien-3,14,17-trione (0.950g., 70%-80% pure) in anhydrous methanol (50 ml.) was added an amount ofsodium methoxide sufficient to obtain the pH range of 8-9.5. Afterapproximately 2 hours, when the production of14β-hydroxy-4,6,9(11)-androstatrien-3,17-dione ceased, as determined bythin-layer chromatography, the mixture was neutralized with acetic acid,the methanol was evaporated, and the residue was chromatographed onsilica using chloroform and 5% acetone as eluent to afford 0.3 g. of theandrostatriene, m.p. 219°-225° (dec.), in 30% yield based on8,14-seco-4,9(11)-androstadien-3,14,17-trione.

I.R. (CHCl₃): 3600 (OH), 3400 (OH), 1745 (C═O), 1660 (C═C--C═O), 1625,1585 (C═C) cm⁻¹ ; U.V.: 282.5 nm, ε=18,500; N.M.R. (CDCl₃): δ 1.14 (s,3H, CH₃), 1.36 (s, 3H, CH₃), 3.25 (m, 1H at C-8), 5.52 (m, 1H at C-11),5.8 (s, 1H at C-4), 6.46 (m, 2H at C-6 and C-7). M.S.: m/e 298.

EXAMPLE 5 Preparation of 14β-hydroxy-4,9(11)-androstadien-3,17-dione

14β-Hydroxy-4,6,9(11)-androstatrien-3,17-dione (0.200 g.), dissolved in50 ml. of benzene and 10 ml. of ethanol, was hydrogenated over 0.100 g.of 2% palladium-on-strontium carbonate. After 15 ml. of hydrogen hadbeen consumed, the catalyst was filtered, the solvents evaporated andthe residue recrystallized from ether to give 0.170 g. (85%) of theandrostadiene, m.p. 170°-172°.

I.R. (CHCl₃): 3600 (OH), 3460 (OH), 1740 (C═O), 1660 (C═C--C═O), 1620cm⁻¹ (C═C); N.M.R. (CDCl₃): δ 1.07 (s, 3H, CH₃), 1.42 (s, 3H, CH₃), 5.55(m, 1H at C-11), 5.80 (s, 1H, at C-4); (in pyridine D₅), 1.25 (s, 3H,CH₃), 1.33 (s, 3H, CH₃), 5.40 (m, 1H at C-11), 5.90 (s, 1H at C-4), 6.07(s, 1H, OH).

EXAMPLE 6 Preparation of 14β-hydroxy-9(11)-androsten-3,17-dione

To a solution of 14β-hydroxy-4,9(11)-androstadien-3,17-dione (0.200 g.)in 10 ml. of dioxane, 3 ml. of tert. butanol and 150 ml. of liquidammonia was added 0.100 g. of lithium and the mixture was stirred at-35° for 10 minutes. The reaction mixture was then treated with anaqueous solution of ammonium chloride and, after evaporation of ammonia,the mixture was extracted with chloroform. The chloroform layer waswashed with brine and dried with sodium sulfate. Evaporation of thechloroform afforded 14β-hydroxy-9(11)-androsten-3,17-diol which withoutpurification was oxidized in methylene chloride (50 ml.) with pyridiniumchlorochromate (0.300 g.) to the androsten-3,17-dione, which wasisolated from the reaction mixture by passing it through a short silicagel column; yield 0.120 g., m.p. 207°-210°.

N.M.R. (CDCl₃): δ 1.03 (s, 3H, CH₃), 1.22 (s, 3H, CH₃), 5.37 (m, 1H atC-11); I.R.: 3600, 3460 (OH), 1745, 1715 cm⁻¹.

EXAMPLE 7 Preparation of 3β,14β-dihydroxyandrostan-17-one

The hydrogenation of 14β-hydroxy-9(11)-androsten-3,17-dione (100 mg.)was carried out over 50 mg. of platinum oxide in 25 ml. of glacialacetic acid. When consumption of hydrogen had ceased, the catalyst wasfiltered, the solvent was evaporated under vacuum and the product wasisolated by chromatography on silica gel using a mixture of 10% acetonein chloroform to afford 70 mg. (˜70%) of the androstan-17-one, m.p.214°-217°.

I.R. (CHCL₃): 3600, 3460, 1740 cm⁻¹ ; N.M.R. (in CH₃ OD): δ 0.85 (s, 3H,CH₃), 1.01 (s, 3H, CH₃), 3.54 (m, 1H at C-3).

EXAMPLE 8 Preparation of 'β-acetoxy-14β-hydroxyandrostan-17-one

3β,14β-Dihydroxyandrostan-17-one (70 mg.) was dissolved in 5 ml. ofpyridine and treated with 1 ml. of acetic anhydride at room temperaturefor 15 hours. After evaporation of solvents, the residue wascrystallized from ether to give 70 mg. of the acetate, m.p. 182°-184°.

N.M.R. (CDCl₃): δ 0.84 (s, 3H, CH₃), 1.05 (s, 3H, CH₃), 2.03 (s, 3H, CH₃CO), 4.70 (m, 1H at C-3).

EXAMPLE 9 Preparation of1-hydroxy-8a-methyl-1-vinyl-1,2,6,7,8,8a-hexahydro-6-naphthalenone

To a solution of 2.2 g. of1-hydroxy-8a-methyl-1-vinyl-1,2,3,4,6,7,8,8a-octahydro-6-naphthalenonein anhydrous dioxane (220 ml.) was added anhydrous dioxane (40 ml.)containing 2.6% by weight of hydrogen chloride. After stirring at roomtemperature for 10 minutes, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(2.497 g.) was added in one portion and stirring was continued at roomtemperature for 8 hours. The initially dark brown solution faded to avery light yellow color with precipitation of2,3-dichloro-5,6-dicyano-1,4-hydroquinone. The precipitate was collectedand washed twice with methylene chloride. The filtrate was neutralizedwith a saturated sodium bicarbonate solution and dried over sodiumsulfate. Evaporation of solvent followed by chromatography using ethylacetate-hexane (3:1) gave 1.5 g. (72%) of the hexahydro-6-naphthalenone,m.p. 101°-102°.

N.M.R. (CDCl₃): δ 1.30 (s, 3H, CH₃), 5.0-6.3 (m, 6H, olefinic protons);I.R. (CHCl₃): 1660, 1620 cm⁻¹ ; U.V.: λ_(max) 285 nm.

EXAMPLE 10 Preparation of1-(2-chloroethylidene)-8a-methyl-1,2,6,7,8,8a-hexahydro-6-naphthalenone

To a solution of1-hydroxy-8a-methyl-1-vinyl-1,2,6,7,8,8a-hexahydro-6-naphthalenone(0.204 g.) in anhydrous methylene chloride (20 ml.) was added 0.5 ml. ofpyridine. The reaction mixture was cooled in an ice-bath and thionylchloride (150 mg.) was added. After 5 minutes, the reaction mixture wasdiluted with methylene chloride (20 ml.) and water (10 ml.) andneutralized with saturated sodium bicarbonate solution (5 ml.). Theaqueous layer was extracted with methylene chloride (3×25 ml.) and thecombined organic layers were washed with brine and dried over sodiumsulfate. Evaporation of solvent gave 217 mg. of the oily chloride.

N.M.R. (CDCl₃): δ 1.35 (s, 3H, CH₃), 4.14 (d, 2H, J=8 Hz, --CH₂ Cl),3.16 (m, 2H, CH₂), 5.66 (t, 1H, C═CH--CH₂ Cl), 5.76 (s, H, ═CH--C═O),6.26 (m, 2H, CH═CH).

EXAMPLE 11 Preparation of8,14-seco-4,6,9(11)-androstatrien-3,14,17-trione

To a solution of1-(2-chloroethylidene)-8a-methyl-1,2,6,7,8,8a-hexahydro-6-naphthalenone(1.41 g.) in dimethylformamide (30 ml.) was added sodium iodide (0.940g.) under nitrogen. The reaction mixture was stirred at room temperaturefor 10 minutes and the sodium salt of 2-methyl-1,3-cyclopentadione (1.27g.) dissolved in methanol was added. The reaction mixture was stirred atroom temperature for 3 hours. The methanol was evaporated and theinorganic salts precipitated by the addition of ether were filtered andwashed with ether. The filtrate was evaporated to dryness and theresidue chromatographed on silica gel giving 1.11 g. (63%) of theandrostatrien-3,14,17-trione, identical with a sample obtained asdescribed above.

I claim:
 1. A compound of the formula ##STR3## wherein R₁ and R₂ areeach independently lower alkyl and the optical antipodes and geometricalisomers thereof.
 2. The compound of claim 1 wherein R₂ and the hydroxylgroup at C-14 are cis.
 3. The compound of claim 2 wherein R₂ and thehydroxyl group are both β.
 4. The compound of claim 3 which is14≈-hydroxy-4,6,9(11)-androstatriene-3,17-dione.
 5. A process for thepreparation of a compound of the formula ##STR4## wherein R₁ and R₂ areeach independently lower alkyl which comprises contacting a compound ofthe formula ##STR5## wherein R₁ and R₂ are as above with a base.
 6. Theprocess of claim 5 wherein R₁ and R₂ are methyl.
 7. The process of claim5 wherein the base is alkali metal alkoxide.
 8. The process of claim 7wherein the alkali metal alkoxide is sodium methoxide.
 9. A compound ofthe formula ##STR6## wherein R₁ and R₂ are each independently loweralkyl, R₂ and the C-14 hydroxyl group are β and the C-8 hydrogen atom isβand the optical antipode thereof.
 10. The compound of claim 9 which is14β-hydroxy-4,9(11)-androstadiene-3,17-dione.
 11. A process for thepreparation of a compound of the formula ##STR7## wherein R₁ and R₂ areeach independently lower alkyl, and R₂, the C-14 hydroxyl group and theC-8 hydrogen atom are βwhich comprises contacting a compound of theformula ##STR8## wherein R₁ and R₂ are as above with hydrogen in thepresence of a metal hydrogenation catalyst.
 12. The process of claim 11wherein R₁ and R₂ are methyl.
 13. The process of claim 11 wherein themetal hydrogenation catalyst is palladium.
 14. The process of claim 11wherein the reaction is conducted in a medium comprising an aromatichydrocarbon and a lower alkanol.
 15. The process of claim 14 wherein themedium comprises benzene and ethanol.
 16. A compound of the formula##STR9## wherein R₁ and R₂ are each independently lower alkyl and theC-3 and C-17 hydroxyl epimers and optical antipodes thereof.
 17. Thecompound of claim 16 which is 3β,14β,17β-trihydroxy-9(11)-androstene.18. The compound of claim 16 which is3α,14β,17β-trihydroxy-9(11)-androstene.
 19. The compound of claim 16which is 3β,14β,17α-trihydroxy-9(11)-androstene.
 20. The compound ofclaim 16 which is 3α,14β,17α-trihydroxy-9(11)-androstene.
 21. A compoundof the formula ##STR10## wherein R₁ and R₂ are each independently loweralkyl and the optical antipodes thereof.
 22. The compound of claim 21which is 14β-hydroxy-9(11)-androstene-3,17-dione.